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19p13.2 microduplication causes a Sotos syndrome‐like phenotype and alters gene expression
Author(s) -
Lehman AM,
du Souich C,
Chai D,
Eydoux P,
Huang JL,
Fok AK,
Avila L,
Swingland J,
Delaney AD,
McGillivray B,
Goldowitz D,
Argiropoulos B,
Kobor MS,
Boerkoel CF
Publication year - 2012
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/j.1399-0004.2010.01615.x
Subject(s) - sotos syndrome , gene duplication , genetics , haploinsufficiency , biology , gene , copy number variation , macrocephaly , pseudogene , phenotype , genome
Lehman AM, du Souich C, Chai D, Eydoux P, Huang JL, Fok AK, Avila L, Swingland J, Delaney AD, McGillivray B, Goldowitz D, Argiropoulos B, Kobor MS, Boerkoel CF. 19p13.2 microduplication causes a Sotos syndrome‐like phenotype and alters gene expression. Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes n uclear receptor‐binding S u‐var, enhancer of zeste, and trithorax d omain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos‐like phenotype. We evaluated a three‐generation family segregating a Sotos‐like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DN A m ethyl t ransferase gene ( DNMT1 ), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.